PD-L1 (formerly B7-H1) is a B7 family member that is expressed on many cell types, including antigen-presenting cells (“APCs”) and activated T cells (Yamazaki et al. (2002) J. Immunol. 169:5538). PD-L1 binds to both PD-1 (CD279) and B7-1. Both binding of T-cell-expressed B7-1 by PD-L1 and binding of T-cell-expressed PD-L1 by B7-1 result in T cell inhibition (Butte et al. (2007) Immunity 27:111). There is also evidence that, like other B7 family members, PD-L1 can also provide costimulatory signals to T cells (Subudhi et al. (2004) J. Clin. Invest. 113:694; Tamura et al. (2001) Blood 97:1809). Furthermore, expression of PD-L1 on the cell surface has also been shown to be upregulated through IFN-γ stimulation.
The interaction between PD-1 and its ligand partners PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) is an important negative costimulatory signaling pathway involved in the regulation of T cell activation. PD-1 can be expressed on T cells, B cells, natural killer T cells, activated monocytes and dendritic cells (DCs). PD-1 is expressed by activated, but not by unstimulated, human CD4+ and CD8+ T cells, B cells and myeloid cells. Nishimura et al., Int. Immunol. 8: 773-80 (1996); Boettler et al., J. Virol. 80: 3532-40 (2006). There are at least 4 variants of PD-1 that have been cloned from activated human T cells, including transcripts lacking (i) exon 2, (ii) exon 3. (iii) exons 2 and 3 or (iv) exons 2 through 4. Nielsen et al., Cell. Immunol. 235: 109-16 (2005).
Normal human tissues seldom express PD-L1 protein on their cell surface, with the exception of tonsil, placenta, and a small fraction of macrophage-like cells in lung and liver, suggesting that under normal physiological conditions, PD-L1 mRNA is under tight posttranscriptional regulation. In sharp contrast, PD-L1 protein is abundantly expressed on the cell surface in various human cancers, as indicated by Chen & Han, Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J. CLIN. INVEST. 125, 3384-3391 (2015).
PD-L2 expression, on the other hand, is more restricted than PD-L1. For instance, PD-L2 is inducibly expressed on DCs, macrophages, and bone marrow-derived mast cells.
Additionally, several studies show a receptor for PD-L1 that is independent of PD-1. B7.1 has also been identified as a binding partner for PD-L1. Butte et al., Immunity 27: 111-22 (2007). Chemical crosslinking studies suggest that PD-L1 and B7.1 can interact through their IgV-like domains. B7.1:PD-L1 interactions can induce an inhibitory signal into T cells. Ligation of PD-L1 on CD4+ T cells by B7.1 or ligation of B7.1 on CD4+ T cells by PD-L1 delivers an inhibitory signal. T cells lacking CD28 and CTLA-4 show decreased proliferation and cytokine production when stimulated by anti-CD3 plus B7.1 coated beads. In T cells lacking all the receptors for B7.1 (i.e., CD28, CTLA-4 and PD-L1), T cell proliferation and cytokine production were no longer inhibited by anti-CD3 plus B7.1 coated beads. This indicates that B7.1 acts specifically through PD-L1 on the T-cell in the absence of CD28 and CTLA-4. Similarly, T cells lacking PD-1 showed decreased proliferation and cytokine production when stimulated in the presence of anti-CD3 plus PD-L1 coated beads, demonstrating the inhibitory effect of PD-L1 ligation on B7.1 on T cells. When T cells lacking all known receptors for PD-L1 (i.e., no PD-1 and B7.1), T cell proliferation was no longer impaired by anti-CD3 plus PD-L1 coated beads. Thus, PD-L1 can exert an inhibitory effect on T cells either through B7.1 or PD-1.
In the context of human disease, PD-L1 expression has been found in several murine and human cancers, including human lung, ovarian and colon carcinoma and various myelomas (Iwai et al. (2002) PNAS 99:12293-7; Ohigashi et al. (2005) Clin Cancer Res 11:2947-53). PD-L1 has been suggested to play a role in tumor immunity by increasing apoptosis of antigen-specific T-cell clones (Dong et al. (2002) Nat Med 8:793-800). It has also been suggested that PD-L1 might be involved in intestinal mucosal inflammation and inhibition of PD-L1 suppresses wasting disease associated with colitis (Kanai et al. (2003) J Immunol 171:4156-63).
As a result, therapeutic targeting of PD-L1 is an area of intense medical interest. The inhibition of PD-L1 signaling has been proposed as a means to enhance T cell immunity for the treatment of cancer (e.g., tumor immunity) and infection, including both acute and chronic (e.g., persistent) infection. However, because only one targeted anti-PD-L1 therapeutic has received marketing approval from the FDA to date, a significant unmet medical need exists.